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Development of malignant cerebral lymphoma in a patient with systemic lupus erythematosus treated with immunosuppression.

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Development of Malignant Cerebral Lymphoma in
a Patient with Systemic Lupus Erythematosus
Treated with Immunosuppression
Eleanor A. Lipsmeyer
A young woman with a clinical diagnosis of systemic lupus erythematosus
was treated with corticosteroids and azathioprine. Within nine months,
she died of a cerebral reticulum cell sarcoma. Previous reports of lymphoma in patients with systemic rheumatic or “autoimmune disease’’
and in homograft patients undergoing immunosuppression are discussed.
A mechanism of recording cases of malignancy in systemic rheumatic
disease occurring both with and without immunosuppression is advocated.
Malignant lymphoma has been infrequently
reported in patients with systemic rheumatic or
“autoimmune” disease (1-4) but widely noted
in homograft recipients who are receiving immunosuppressive therapy ( 5 , 6). This paper
describes a malignant lymphoma in a patient
who was undergoing immunosuppression for
systemic lupus erythematosus (SLE).
A 27-year-old white woman was hospitalized in July,
1970, with edema, hypertension and proteinuria. She was
found to have pancytopenia, an IgC of 700 mg% and a
serum albumin of 1.5 g%. There was a positive direct
Coombs test, a serum complement (6Ic-la) of 80 mg%, and
a search for LE cells revealed suspicious but no diagnostic
Serum drawn at the onset of her disease and frozen for 14
months, was assayed for antinuclear antibody (ANA) after
her death and was found to be positive at a 1:40 dilution.
(Normal serum demonstrates no ANA at 1:10 dilution.)
Blood urea nitrogen was 42 mg% and a creatinine clearance was 67 ml/min. A percutaneous renal biopsy was interpreted as “changes of nonspecific nephritis.” A clinical
diagnosis of systemic lupus erythematosus was made, and
on August 14, 1970, therapy was initiated with 80 mg/day
is Assistant Professor of Medicine,
Chair of Rheumatology at the University of Arkansas
School of Medicine and Consultant in Rheumatology, Leo
N. Levi Arthritis Hospital, Hot Springs, Arkansas.
Despite continuing steroids, proteinuria of 7.5 g/24 hr
and hemolysis (hematocrit of 23%; reticulocyte count of
14%) persisted. On September 3, 1970, azathioprine (Imuran), 200 mg/day was begun. This was gradually decreased until on September 30, 1970, she was receiving 60
mg/day prednisone and 50 mg/day azathioprine.
On October 19, 1970, id the outpatient clinic, the patient
reported that she was completely blind in her right eye.
Funduscopic examination on the right showed the arteries
were completely white. T h e disc was pale, and thought to
represent optic atrophy after retinal artery occlusion. The
left fundus revealed retinal edema and severe periarteric
change of the vessels as they left the disc. Vision gradually
deteriorated in the left eye, until complete blindness occurred.
She continued prednisone, 100 mg/day, and azathioprine, 100 mg/day, until on November 9, 1970, she developed left chest pain and was readmitted to the hospital. A
lingular infiltrate was seen on the chest film. Multiple
pulmonary infiltrates then appeared, and on November 19,
open lung biopsy revealed cytomegalic inclusion disease.
Azathioprine was discontinued and prednisone tapered to
10 mg/day. The pulmonary infiltrates resolved with these
changes in therapy.
On January 11, 1971, she was admitted to the hospital
with a gradual onset of paraplegia. Myelography revealed a
mass at T-3 and she underwent decompression laminectomy at T-2 through T-4. An epidural abscess was drained
and Aspergiffusfumigatus was cultured from the purulent
material. Septate hyphae were seen on tissue sections. She
received 1.6 g Amphotericin B intravenously over the next
three months. Despite laminectomy, paralysis from T-3
down persisted.
Arthritis and Rheumatism, Vol. 15. No. 2 (March-April 1972)
epidural abscess with Aspergillusfumigatus, for
which Amphotericin B was given.
In retrospect, blindness may have been the
first manifestation of her lymphoma since the
right optic tract showed tumor cell infiltration
at autopsy. However, her attending physicians
attributed the blindness to her SLE since the
funduscopic findings were compatible with the
retinal vessel perivasculitis which may develop
in this disease (9).
T h e association of malignant lymphoma and
rheumatic disease was described by Cammarata, Rodnan and Jensen(1) who reviewed the
literature in 1963 and found 8 previously recorded cases and added 4 new cases. Three
cases of lymphoma occurred in SLE and one in
association with rheumatoid arthritis. A year
later, Tala1 and Bunim (2) described the
development of malignant lymphoma in 4 of 58
patients with another “autoimmune” disease,
Sjogren’s syndrome. In addition to the usual
fairly benign manifestations of keratoconjunctivitis sicca, xerostomia and parotid enlargement, these patients had a high incidence of
splenomegaly, purpura, vasculitis and lymphopenia, probably indicating a systemic disease.
Of the patients in both these reports,
four received corticosteroids; none received
azathioprine. Three other patients with SLE
terminating in lymphoreticular neoplastic
disease have since been described (3, 4). All had
been treated with corticosteroids and chloroBecause the clinical diagnosis of SLE was quin.
T h e association of leukemia and lymphoma
based on hemolytic anemia, pancytopenia, decreased serum complement and nephritis with with “autoimmune disease”, including SLE
nephrotic syndrome, this patient was given and rheumatoid arthritis, was investigated by
large doses of corticosteroids. When hemolysis Oleinick (10) who reviewed published case repersisted, azathioprine was added to the ports through 1965. Using age-specific mortherapy (7), and given for 4 months. Cortico- tality rates, he found that the observed number
steroids were given for a total of 9 months. of deaths from lymphoma and leukemia in these
She did not receive antilymphocyte serum, diseases was no greater than the predicted
a n d throughout her illness required only mortality in the general population.
three units of whole blood.
T h e well known infectious complications (8) Schwartz (1 1) predicted the increase in maligof immunosuppression, which occurred in this nant change in patients undergoing immunopatient, included cytomegalic virus disease and suppression, many cases of lymphoma have
On May 4, 1971, she returned with a flaccid paralysis of
the left face and arm. She died the following day of respiratory failure.
At autopsy, the lungs revealed a diffuse pneumonic process with consolidation and necrosis. Cytomegalic inclusion
bodies were not present. There was one microabscess containing budding yeast with septate hyphae. The heart was
normal except for a very thin layer of fibrin over the pericardial surface. The liver and spleen were normal.
Multiple kidney sections showed intimal thickening and
medial hypertrophy of arterioles. The glomeruli showed
basement membrane thickening with some areas suggestive
of “wire loop change”. Rarely, there was synechia formation between the glomerular tuft and Bowman’s capsule.
Focal interstitial infiltrates of mononuclear cells were seen.
The tubules were normal.
The adrenal glands showed decrease in size with cortical
thinning and loss of lipid from cortical cells.
Sections of the right temporal lobe of the brain revealed
large areas of tissue replaced by sheets of polygonal cells
with vesicular nuclei containing one or more nucleoli. Mitotic figures were frequent. In some areas the tumor cells
were infiltrating and replacing the walls of vessels. The
picture was consistent with a reticulum cell sarcoma type of
malignant lymphoma.
Sections through the optic chiasm revealed diffuse atrophy of the optic nerve and tract with accumulation of many
lipid-filled macrophages. The right optic tract and nerve
were infiltrated by tumor cells similar to those in the brain.
Section of the eye showed atrophy of the optic nerve associated with a moderate mononuclear cell infiltrate.
Section of the spinal cord at T-2 showed complete obliteration of the architecture by extradural fibrous tissue.
Occasional fungi, similar tn those found in the pulmonary
sections, were noted.
Atthritis and Rheumatism,Vol. 15, No. 2 (March-April 1972)
been reported in homograft transplant recipients receiving this type of medication. In review
of data from a n informal registry of 5170
transplantation patients, a total of 52 de ROUO
malignancies was noted (5). Of the 22 lymphomas reported, 11 (50%) arose in the brain.
Azathioprine and prednisone had been used in
all patients; only 3 received antilymphocyte
Thus far, there appears to be only one reported case of development of a lymphoma by a
patient receiving immunosuppressive drugs for
reasons other than homograft transplantation.
In 1969, Sharpstone et a1 (12) recorded a
lymphosarcoma in a patient who was being
treated with prednisolone and azathioprine for
nephrotic syndrome due to proliferative glomerulonephritis.
Possible causes for the high incidence of
lymphomas occuring in the cranial vault may be
the relative inaccessibility of the brain compartment to circulating antibodies and lymphocytes. Green (13) reported that human tumor tissue was easily transplanted to the brain
of various animals and was accepted without
signs of rejection.
Uninhibited replication of oncogenic virus in
patients receiving immunosuppressive therapy
must be considered. These patients are quite
susceptible to viral infections, and the possibility of a viral cause of rheumatic or autoimmune
disease is still debated. Virus-like inclusion
particles have been noted in renal biopsies from
patients with SLE (14) but their significance is
still unknown. Recently, Evans el a1 (15) have
shown increased titers to Epstein Barr (EB)
virus in SLE. Increased titers of antibody to EB
virus are also present in the sera of patients
with such neoplastic tumors as Burkitt lymphoma (16) and carcinoma of the nasopharynx (17). While E B virus has not been
shown to be the causative agent in these
diseases, speculation still persists about the
significance, if any, of these antibody titer rises.
Thomas (8) has stated that the function of the
cellular immune system (delayed hypersensi-
tivity) is the recognition and rejection of mutant
and other abnormal cells as though they were a
homograft. Burnet (19) has coined the term
“immunological surveillance” to denote this
function. When the cellular immune system is
impaired by immunosuppressive drugs, it is
likely that the body is no longer able to reject
malignant cells as they arise; they continue to
grow and divide unhindered.
If, indeed, there is a predisposition to malignancy in rheumatic or autoimmune disease, our
use of immunosuppression in these patients
should be re-evaluated, since the impairment of
the cellular immune system may allow growth
of oncogenic virus or survival of neoplastic tissue if it arises.
T o gain insight into this problem, we woltld
recommend that the American Rheumatism
Association consider establishing a registry,
similar to the registry for transplantation patients, for recording of malignancies which
develop in patients with rheumatic or autoimmune disease whether or not they have been
given immunosuppressive drugs. We would also request that various centers throughout the
country review and report their experience with
any similar patients.
1. Cammarata R J , Rodnan GP, Jansen WW: Systemic rheumatic disease and malignant lymphoma. Arch Intern Med 1 1 1 :330-337, 1963
2. Tala1 N , Bunim J J : The development of malignant lymphoma in the course of Sjijgren’s
syndrome. Am J Med 36:529-540,1964
3. Nilsen LB, Missal ME, Condemi JJ: Appearance of Hodgkin’s disease in a patient with systemic lupus erythematosus. Cancer 20: 19301933,1967
4. Andreev VC, Zlatkov NB: Systemic lupus erythematosus and neoplasia of the lymphoreticular system. Br J Derm 80:503-508, 1968
5. Schneck SA, Penn I: De novo brain tumours in
renal-transplant recipients. Lancet 1 :983-986,
6. Doak PB, Montgomerie JZ, North JDK, et al:
Reticulum cell sarcoma after renal homotrans-
Arthritis and Rheumatism, Vol. 15, No. 2 (March-April 1972)
plantation and azathioprine and prednisone
therapy. Br Med J 4:746-748,1968
Parker CW, Vavra JD: Immunosuppression.
Progress in Hematology 6:1-81, 1969
Starzl TE, Porter KA, Andres G, et al: Long
term survival after renal transplantation in humans. Ann Surg 172:437-472,1970
Duke-Elder S, Dobree JH: System of Ophthalmology. Vol 10. Diseases of the Retina. First
edition. St Louis, CV Mosby Co, 1967, pp
Oleinick A: Leukemia or lymphoma occurring
subsequent to an autoimmune disease. Blood
29:144-153, 1967
Swanson MA, Sehwartz RS: Immunosuppressive therapy. New Engl J Med 277:163-170,
Sharpstone P, Ogg CS, Cameron JS: Nephrotic
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Greene HSN: The transplantation of tumors to
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1 1:529-534, 1951
14. Grausz H, Earley LE, Stephens BG, et al:
Diagnostic import of virus-like particles in the
glomerular endothelium of patients with systemic lupus erythematosus. N Engl J Med
15. Evans AS, Niederman JC, Rothfield NF: EB
virus and other viral antibody levels in systemic
lupus erythematosus. Arthritis Rheum 14:160,
16. Henle G, Henle W, Clifford P, et al: Antibodies
to Epstein-Barr virus in Burkitt’s lymphoma
and control. groups. J Nat Cancer Inst
17. Henle W, Henle G, Ho HC, et al: Antibodies to
Epstein-Barr virus in nasopharyngeal carcinoma, other head and neck neoplasms, and control
groups. J Nat Cancer Inst 44:225-231, 1970
18. Thomas L: Discussion of Medawar, PB: Reactions to Homologous Tissue Antigens in Relation to Hypersensitivity. Cellular and Humoral
Aspects of the Hypersensitive State. Edited by
HS Lawrence. New York, Hoeber Medical Division, Harper and Row, 1959, pp 529-532
19. Burnet F M : Immunological aspects of malignant disease. Lancet 1 : 1171-1 174, 1967
Arthritis and Rheumatism, Vol. 15, No. 2 (March-April 1972)
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development, lupus, patients, systemic, immunosuppressive, malignant, erythematosus, treated, cerebral, lymphoma
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